This application proposes to study the role of cytokines in tumor growth and the factors responsible for cytokine mRNA stability in tumor cells. Cytokine mRNAs are unusually stable in cultured tumor cells and tumor xenografts in mice. Specific aims: 1) To determine the physiological implications of stable cytokine mRNAs in tumor cells using recombinant cytokines, anticytokine antibodies and antisense DNA. 2) To study the factors which control mRNA stability using similar techniques and focusing on the role of cytokines such as IL-1, TGFb, TNF, GM-CSF, IL-6. 3) To study the mechanism of stabilization of cytokine mRNA in tumors using RNA gel retardation, footprinting, and in vitro polysome systems to look for possible RNA binding proteins and to determine the structural sequences important in stability. 4) To study the production of factors which regulate RNA stability using protein biochemistry and the polysome system. Phase I of this project will be devoted to completing specific aims 1&2 and mastering RNA gel retardation and footprinting. Phase II will apply the techniques learned in Phase I to the identification and isolation of an RNA binding protein and identification of factors responsible for RNA stability. Phase II will also attempt to confirm the results obtained for cultured cells and xenografts by examining fresh tumor specimens. Long term goals include isolating and sequencing the binding protein which would enable cloning of its gene and a detailed study of its regulation. It has been suggested that cytokines may play a role in tumor growth perhaps via autocrine stimulation or via other mechanisms. An understanding of the increased stability of cytokine mRNA in tumor cells may lead to the ability to control cytokine levels in these cells and a therapeutic approach to controlling tumor growth in cancer patients.